What is HIV antiretroviral drug treatment

8/7/2019 What is HIV antiretroviral drug treatment

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Integrase Inhibitors 2007

Integrase inhibitors interfere withthe integrase enzyme, which HIVneeds to insert its genetic materialinto human cells.

NRTIs and NNRTIs are available in most countries. Fusion/entry inhibitors and integraseinhibitors are usually only available in resource-rich countries.

Protease inhibitors are generally less suitable for starting treatment in resource-limited settingsdue to the cost, number of pills which need to be taken, and the particular side effects caused byprotease drugs.

Combination Therapy

Taking two or more antiretroviral drugs at a time is called combination therapy. Taking acombination of three or more anti-HIV drugs is sometimes referred to as Highly ActiveAntiretroviral Therapy (HAART).

Why do people need to take more than one drug at a time?

If only one drug was taken, HIV would quickly become resistant to it and the drug would stopworking. Taking two or more antiretrovirals at the same time vastly reduces the rate at whichresistance would develop, making treatment more effective in the long term.

What does combination therapy usually consist of?

The most common drug combination given to those beginning treatment consists of two NRTIscombined with either an NNRTI or a "boosted" protease inhibitor. Ritonavir (in small doses) ismost commonly used as the booster; it enhances the effects of other protease inhibitors so theycan be given in lower doses. An example of a common antiretroviral combination is the twoNRTIs zidovudine and lamivudine, combined with the NNRTI efavirenz.

Some antiretroviral drugs have been combined into one pill, which is known as a fixed dosecombination. This reduces the number of pills to be taken each day.

The choice of drugs to take can depend on a number of factors, including the availability and

price of drugs, the number of pills, the side effects of the drugs, the laboratory monitoringrequirements and whether there are co-blister packs or fixed dose combinations available. Mostpeople living with HIV in the developing world still have very limited access to antiretroviraltreatmentand often only receive treatment for the diseases that occur as a result of a weakenedimmune system. Such treatment has only short-term benefits because it does not address theunderlying immune deficiency itself.
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First and second line therapy

At the beginning of treatment, the combination of drugs that a person is given is called first linetherapy. If after a while HIV becomes resistant to this combination, or ifside effects areparticularly bad, then a change to second line therapy is usually recommended.

Second line therapy will ideally include a minimum of three new drugs, with at least one from anew class, in order to increase the likelihood of treatment success.

Choosing when to start antiretroviral treatment is a very important decision. For treatment inresource-poor countries, the World Health Organisation recommends a first line regimen of oneNNRTI and two NRTIs, such as AZT or tenofovir combined with 3TC or FTC.6 Americanguidelines recommend one NNRTI or a PI combined with two NRTIs.7

Once treatment has begun it must be adhered to, in spite of side effects and other challenges.Many factors must be weighed up when deciding whether to begin treatment, including the

results of various clinical tests.

When to start antiretroviral treatment?

Before a person starts treatment it is recommended that a basic clinical assessment should becarried out. This should include determination of existing medical conditions (such as hepatitis,TB, pregnancy, injecting drug use and major psychiatric illness), assessment of currentmedications (including traditional and herbal medications), weight measurement, and assessmentof patient readiness for therapy. If AZT is being considered then a haemoglobin measurementshould be taken, and a pregnancy test should be taken if EFV is being considered.

The CD4 test

Where available, the CD4 test is used to determine when a person should start treatment.

HIV attacks a type of immune system cell called the T-helper cell. This cell carries on its surfacea protein called CD4, which HIV uses to attach itself before gaining entry to the cell.

The T-helper cell plays an important part in the immune system by helping to co-ordinate all theother cells to fight illnesses. A major reduction in the number of T-helper cells can have a seriouseffect on the immune system. HIV causes many T-helper cells to be damaged or destroyed; as a

result, there are fewer cells available to help the immune system.

A CD4 test measures the number of T-helper cells (in a cubic millimetre of blood). Someoneuninfected with HIV normally has between 500 and 1200 cells/mm3. In a person infected withHIV the CD4 count declines over a number of years. Treatment is generally recommended whenthe CD4 test shows fewer than 350 cells/mm3.1234 However, guidelines vary slightly betweencountries and these are constantly debated.
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When the CD4 count reaches the recommended level to start treatment, other factors may also betaken into account, such as viral load and opportunistic infections

WHO clinical staging of HIV disease

The World Health Organisation (WHO) has a method of describing the different stages of HIVdisease based on clinical symptoms, known as the WHO staging system for HIV disease. TheWHO 2009 treatment guidelines state that where CD4 testing is unavailable, the WHO stagingsystem should be used to determine whether to start treatment.5 Where a patient is showing signsof WHO clinical stages 3 or 4 they should start treatment and if they are showing signs of stages1 and 2 they should not start treatment. In places where CD4 tests are available, the WHOrecommend that treatment is started if the CD4 count is 350 cells/mm3 or below, regardless of theWHO clinical stage.

Opportunistic infections

As the immune system becomes increasingly damaged by HIV it is more susceptible toopportunistic infections. These infections would usually be fought off by a healthy immunesystem, but a low CD4 cell count means opportunistic infections such as PCP (a type ofpneumonia) can be life-threatening. If one of these illnesses becomes a serious problem,antiretroviral treatment may be advised immediately.

Choosing The Best Combination

The following issues need to be considered before starting treatment

The effectiveness of the combination

Some combinations of antiretrovirals are more effective than others. Taking drugsrandomly from the different ARV groups may result in a weak combination that doesntsuppress the HIV infection sufficiently, ending in drug resistance. A few drugs haveharmful effects when used together and should not be combined (an example is stavudineand zidovudine)

Number of pills and frequency of dosage

Some combinations - especially those involving a protease inhibitor - require swallowing

many pills throughout the day, which some people find hard to do. The size of the pillscan also be an issue. One option for reducing the pill burden may be to take a FDC (fixeddose combination), which combines two or more drugs in a single tablet or capsule.

Food restrictions : There are a few drugs, particularly protease inhibitors, which haveto be taken with food to improve absorption rates. Some other drugs have to be taken on
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Pregnancy and treatment

Many studies have shown that antiretroviral drugs can be used during pregnancy. The drugs canbe used to reduce a woman's viral load effectively below detection. This also greatly reduces therisk of the baby becoming infected.

Treatment for children

The progression of HIV in children is monitored through viral load and CD4 tests, as with adulttreatment, but because the CD4 and viral load levels vary in children (especially between ages 1to 4) they must be treated on an individual basis. CD4 counts in children are generally muchhigher than in adults, and change with the childs age. This means that adult guidelines on whento start antiretroviral treatment do not apply.

MONITORING TREATMENT SUCCESS

The viral load test

It is done to track how well ARV is working.Viral load refers to the amount of HIV in the blood.If the viral load is high, T-helper cells tend to be destroyed more quickly. The aim ofantiretroviral treatment is to keep the viral load as low as possible.

A viral load test is carried out shortly after antiretroviral treatment is started. If the treatment isworking effectively, the viral load will drop to the undetectable level below 50 copies/ml.Ideally this will happen within 24 weeks of starting treatment, but for some it can take 3 to 6months. Some people never reach undetectable.

Viral load tests are then carried out every few months.. An increase in viral load may befollowed by a fall in CD4 count and a greater risk of developing opportunistic infections.

If viral load is increasing it is important to determine whether the treatment is failing due to drugresistance, poor adherence or drug interactions.

Other assessments after starting treatment

Once therapy has begun, there should be additional clinical and laboratory monitoring, including:

Assessment for signs/symptoms of potential drug toxicities Adherence counselling and assessment of adherence Assessment of response to therapy and signs of treatment failure Weight measurement CD4 testing at least every six months (if available) Haemoglobin monitoring for patients on AZT
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In resource-poor communities it is recommended that this monitoring should take place 2, 4, 8,12 and 24 weeks after treatment begins and then every six months once the patient has stabilisedon therapy.

Drug resistance

Antiretroviral drugs slow the replication of HIV in the body. However the drugs cannot stop thereplication completely, so some HIV is able to survive despite ongoing HIV treatment.

When HIV replicates it often makes slight mistakes, so each new generation of HIV differsslightly from the one before. These tiny differences in the structure of HIV are called mutations.Some of the mutations occur in the parts of HIV that are targeted by antiretroviral drugs. Soalthough there is some HIV that continues to be attacked by the drugs, there are otherstrains ofHIV that are less likely to be affected. This HIV is called drug resistant HIV, and it is able toreplicate unaffected by the drugs.

When someone has drug resistant HIV (commonly referred to as drug resistance), the amount ofHIV in the blood rises and the risk of the person becoming ill increases. Drug resistance is one ofthe main reasons why antiretroviral treatment fails. If resistance develops, usually the drugregimen needs to be changed.

Avoiding and detecting resistance

Taking medication exactly as prescribed is a very important part of avoiding resistance.

Taking a combination of 3 or 4 drugs ensure that the drug combination is strong to beginwith will lessen the risk of resistance developing

Missing doses or not taking them on time lowers the amount of antiretroviral chemicalsin the body, which means the virus is not properly suppressed. The virus is then able toreplicate faster, increasing the chance of it becoming resistant

Regular viral load testing is also important & an increasing viral load can be a sign ofgrowing drug resistance.

Cross-resistance

If HIV is resistant to one drug, it will sometimes be resistant to similar drugs in the same group.This is called cross-resistance and it means that some antiretroviral drugs will not work even ifthey have not been used before.

Drug interactions

Interactions between certain antiretroviral drugs and other drugs, both pharmaceutical andrecreational, can alter the effectiveness of antiretroviral therapy. Interactions may lower theamount of antiretroviral drugs absorbed, allowing low level HIV replication to occur, which mayincrease the risk of drug resistance.
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ARVs may interact with the following types of drugs:

Other antiretrovirals. An ongoing study has found that Invirase (saquinavir) whencombined with Norvir (ritonavir) may cause an abnormal heart rhythm by affecting theheart's electrical signals.1 Symptoms can range from lightheadedness to an abnormal

heartbeat with the possibility that more severe side effects will develop such asventricular fibrillation.

Other pharmaceutical drugs.. It is not recommended that protease inhibitors be takenwith drugs such as Cafergot and Migranal, which are used to treat migraine headaches.Women living with HIV taking oral contraceptives and/or hormone replacement therapyneed to talk to their doctor about possible drug interactions.

Herbal and complementary treatments. Garlic capsules, for example, stop saquinavir -a protease inhibitor - from working properly.

Drugs for treating opportunistic infections. For example the tuberculosis treatmentRifabutin should usually not be used with the protease inhibitor Saquinavir or the NNRTI

delavirdine.4

SIDE EFFECTS

Most of the antiretroviral drugs have known side effects, but this does not mean that everyonewho takes the drugs will experience them. Some people only experience mild side effects andfind them easily manageable. But for some the side effects occur so strongly that they have toconsider alternative drugs.

The side effects often get better after a person has been on treatment for a while, as the bodystarts to adjust to the antiretroviral drugs.

Side effects are often referred to by the grade of the effect, and the grades range from mild tomoderate to severe to life-threatening. For example, it is considered a mild side effect if a personhas 2-3 vomiting episodes a day. Life-threatening side effects such as extreme limitations indaily activity and hospitalisation are rare, but are still threats to some.5

The side effects often get better after a person has been on treatment for a while, as the bodystarts to adjust to the antiretroviral drugs. Doctors can usually prescribe some treatment to helpwith the most common side effects such as nausea and diarrhoea.

Some people use alternative therapies and medications with combination therapy to ease the

side effects. For example, ginger for some may ease nausea.6 Sometimes the side effects donot diminish over time; in some instances one or more of the drugs in the combination canbe changed to reduce the side effects.
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Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS is an illness that occurs for a small number of patients soon after treatment is started. It iscaused by an excessive response by the recovering immune system to opportunistic infectionsthat were already present, but were previously dormant and not producing symptoms. Although

the symptoms of IRIS are often mild, occasionally they can be life threatening. Generally thosewho have a severely damaged immune system before starting antiretroviral treatment are more atrisk of developing IRIS.

IRIS does not indicate that treatment is failing. Usually the best response to IRIS is to continuetreatment; the symptoms normally disappear within a few weeks. In cases involving severeopportunistic infections, such as cryptococcal meningitis or tuberculosis, it may be necessary tostop antiretroviral therapy whilst the infection is treated

Adherence

The term adherence means taking all of the medication at the right time and exactly as thedirections state. It also means ensuring that there will be no interactions with other drugs beingtaken.

Anything below 95 percent adherence has been associated with increases in viral load and drugresistance.7 Therefore adherence to antiretroviral treatment is extremely important. This meansmissing no more than one dose a month, if taking antiretroviral drug treatment once a day.

Often experiencing side effects makes adherence difficult. As adherence is such a vital part oftreatment, it is important to monitor closely the impact that side effects may have on adherence.

A patient should inform their doctor if side effects are affecting adherence or if it is difficult tostick to a drug regimen.

Changing HIV treatment

Side effects and treatment failure are the two main reasons why antiretroviral treatment mayneed to be changed.

Side effects

Sometimes side effects can be so strong, intolerable or even life-threatening that the treatment

must be changed. In such cases it is normally safe to change only the offending drug(s).Antiretroviral drug side effectshas more information.

Why do HIV Treatment fail??

A change of treatment is needed when the antiretrovirals fail to slow down the replication of thevirus in the body. This can occur as a result of drug resistance, poor adherence, poor drug
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absorption or a weak combination of drugs. Increased viral load or an HIV-related illness may besigns of failing antiretroviral treatment.

There are different opinions about when to change treatment if viral load is increasing. Somedoctors recommend changing as soon as the viral load starts to rise, although this could mean

running out of treatment options more quickly. Others recommend monitoring the trend of theviral load before making a decision to change. This latter approach may increase the risk ofdeveloping resistance to certain drugs, which can limit future treatment options.

The changes made to the drug regimen will depend on the drugs already being used, the CD4count and the patients general health.

If viral load testing is not available it can be difficult to identify treatment failure. The WorldHealth Organisation (WHO) has developed a staging system for HIV disease based on clinicalsymptoms, which may be used to guide medical decision making..

WHO guidelines state that treatment failure may be signified by a new or recurrent Stage IVcondition occurring after at least six months of therapy.8 Conditions occurring before this timeoften represent immune reconstitution syndrome. The onset or recurrence of certain Stage IIIconditions such as pulmonary TB and severe bacterial infections after at least six months oftreatment may also indicate treatment failure. Some Stage IV conditions, such as lymph nodeTB, may not be indicators of treatment failure.

Combined with clinical judgement, the following table can guide the decision of whether to

switch treatment.

Treatment

failure criteriaWHO Stage I WHO Stage II

WHO

Stage III

WHO

Stage

IV

Clinical (CD4

testing

unavailable)

Do not switch Do not switchConsider

switchingSwitch

CD4 failure (viral

load testing

unavailable)

Do not switch

repeat CD4 testin three months

Do not switch

repeat CD4 testin three months

Consider

switchingSwitch

CD4 failure and

viral load failureConsider switching Consider switching Switch Switch

In 2008 a study concluded that these guidelines only effectively detected treatment failure in aminority of patients.9The majority of those identified as having treatment failure by clinical
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criteria or CD4, in fact had adequate viral load suppression and therefore did not need to changetreatment. However without viral load testing, these guidelines are the most helpful way ofrecognising treatment failure.

Salvage therapy

Salvage therapy is the term often used to describe the treatment for those who are resistant todrugs in the three main drug classes. In this situation it may be difficult to find a drug regimenthat suppresses the viral load to undetectable.

Many people start their salvage therapy with a much higher viral load than when they startedprevious HIV treatments. This puts more pressure on the new combination to work. Eachcombination used lessens the chance of maintaining a low viral load because of the possibility ofdeveloping resistance to the drugs. The choice of new treatment should always depend on whatcaused the previous one to fail.

The recent introduction ofnew classes of drugs has meant that there are more alternativecombinations for those who were running out of treatment options.

Structured Treatment Interruptions (STIs)

A Structured Treatment Interruption (STI) is when someone stops taking antiretroviral treatmenttemporarily. Sometimes people have to stop treatment due to severe side effects, ineffectivenessof the drugs or psychological issues. Taking an STI does not mean skipping or stoppingmedication randomly, but taking a break from the drug regimen with a planned timescale andclose monitoring from a doctor.

UK and American treatment guidelines do not recommend taking planned treatment breaksunless under clinical trial settings. Studies have shown that some types of STI have beenassociated with an increased short-term risk of HIV disease progression.10

HIV transmission and antiretroviral drugs

Although antiretroviral drugs suppress HIV, they have not been proven to stop transmission,even when the viral load is undetectable. Unprotected sex between two HIV positive people isnot a risk-free activity; there are many different strains of HIV and it is possible to becomeinfected more than once, which can complicate treatment. Those taking antiretroviral drugs

should take as much care to minimise the risk of HIV transmission as they did before starting thetreatment.

Reducing the price of HIV/AIDS treatment
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Access to antiretroviral (ARV) treatment in

Botswana

In 1996, HAART - an effective combination therapy that delays the onset of AIDS - becameavailable to those living with HIV in rich countries2. Within four years, death rates for peoplewith HIV/AIDS in developed countries had dropped by 84%.3

At a cost of US$10,000-15,000 per person per year, these antiretroviral drugswere far tooexpensive for the majority ofHIV infected people in resource poor countries. Five years afterHAART was introduced in the West, fewer than 8,000 people in sub-SaharanAfricawerereceiving the life-saving drugs.4 In order for treatment to reach people living with HIV in thedeveloping world, the price of the drugs clearly needed to come down to an affordable level.

At the beginning of the new millennium there was a breakthrough in treatment provision forresource poor areas when an Indian pharmaceutical company started to produce genericantiretrovirals that were exactly the same as those made by large pharmaceutical companies, butsignificantly cheaper. This sparked a price war between branded and generic drug makers, which

forced the large pharmaceutical companies to lower the price of their AIDS drugs. Thiscompetition, coupled with pressure from activists, organisations - such as the Clinton Foundation- and governments of poor countries with severe AIDS epidemics, dramatically reduced the priceof ARVs for developing countries. By the middle of 2001, triple combination therapy wasavailable from Indian generic manufacturers for as little as $2955.

The price of antiretrovirals for low- and middle-income countries has continued to fall. Between2004 and 2008, first-line antiretroviral regimens in lower- and middle-income countries declinedby 30-68%. The most widely used drug combination (d4T+3TC+NVP) is available for $US 88per person per year.6

The role that generic drug production and price negotiations with multinational pharmaceuticalcompanies played in lowering the price of antiretrovirals will now be looked at in more detail.

Generic drugs

A generic drug is an identical copy (bioequivalent) of a brand name (or proprietary) drug.Generics are exactly the same as their branded counterparts in dosage form, safety, strength,
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route of administration, quality, performance characteristics and intended use. The notabledifference between the two is the price.

Generic drug manufacturers incur fewer costs in creating the generic drug, as they do not have tocover the expense of drug discovery, or lengthy safety and efficacy trials. Instead generic makers

reverse-engineer known drug compounds. This means that generic manufacturers are able tomaintain profitability while offering the drug at a much lower cost.

This is problematic for pharmaceutical companies who argue that generic copying reduces theirprofits and decreases the amount of money they can spend on researching and developing newAIDS drugs. In order for the proprietary drug makers to recoup the money they spent on drugcreation, they are granted a patent (an intellectual property right), which is an exclusive rightthat prevents others from making, using, selling, offering to sell, or importing their drug. Thepatent typically lasts for twenty years.

Legislation in favour of the pharmaceutical industries right to patent their drugs - TRIPS - was

introduced in 1995. TRIPS - The Agreement on Trade Related Aspects of Intellectual PropertyRights introduced intellectual property law into the international trading system for the firsttime and applies to all members of the World Trade Organization (WTO). Because theimplementation of TRIPS was to have a huge impact on generic drug production, the majority ofdeveloping countries were given a ten-year transition period in which to comply. This means thatdeveloping countries (such as India) were able to continue developing generic drugs until 2005,whilst least developed countries have until 2016.

Generic drugs, FDCs and AIDS

In 2001, Indian generic drug manufacturer, Cipla, announced that it would sell a generic copy of

a triple-therapy antiretroviral for US$350 per patient per year. This had an incredible impact asthe competition this generated dramatically drove down the price of anti-AIDS drugs fordeveloping countries, thereby increasing the range of affordable options for national treatmentprogrammes.

The graph below illustrates the effect of generic competition on proprietary drug prices between2000 and 2001. It shows the lowest world price per patient per year of triple combination therapymade up of d4T (stavudine) + 3TC (lamivudine) + nevirapine7.

India is the largest supplier of generic ARVs to low- and middle- income countries, providing 80% of donor-funded ARVs to low and middle income countries.8Brazil,Thailand andSouthAfrica also produce a significant amount of generic drugs and a number of African nations - suchas Zambia, Ghana, Tanzania, UgandaandZimbabwe - have developed local AIDS drugmanufacturing facilities9 In 2008 UNAIDS reported that national governments of 94% ofcountries with generalised epidemics, and 61% of countries with concentrated epidemics, hadnational policies for using generics to promote antiretroviral access10.
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The manufacture and export of generic drugs was not only a turning point in terms of the price ofARVs, but also helped to revolutionise treatment for resource-poor settings by simplifyingHIV/AIDS treatment. In 2001, an Indian generic manufacturer produced a combination of threeantiretrovirals (patented by different pharmaceutical companies) into a single pill, known as afixed dose combination (FDC). This was only possible because India did not have to abide by

TRIPS legislation at this time and was therefore able to ignore the patents on the drugs.

FDCs were a significant innovation as they reduce the number of pills taken each day. BecauseFDCs are easier to manage for both patients and health workers they increase adherence,thereby reducing the incidence ofdrug resistance. The drugs were also available in heat resistantforms, which proved extremely valuable for use in the developing world, where often there isscarce access to refrigeration facilities.

Generic antiretrovirals are now widely used to treat HIV/AIDS in the developing world. Theyhave been integrated into many treatment programmes including PEPFAR- the President'sEmergency Plan for AIDS Relief. PEPFAR, the single greatest supporter of treatment provision

for AIDS in the developing world, began to distribute generic drugs through its programmes in2004-5. In 2007, generics accounted for 57% of the $131 million PEPFAR spent on anti-AIDSdrugs11.

The role that the production of generic drugs had on the distribution of treatment for developingcountries cannot be underestimated. Quite simply, as Stephen Lewis, former UN Special Envoyfor AIDS in Africa, has said: we wouldnt have this extraordinary run of treatment in Africanow if it werent for the generic drugs.12

Pressure and negotiation with Big Pharma

In the early 2000s, large pharmaceutical companies (known as Big Pharma) manufacturingdrugs to treat HIV/AIDS were subject to intense pressure to lower their prices. Organisationssuch as the Clinton foundation, Mdecins Sans Frontires and (more recently) UNITAID,alongside AIDS activists and a number of national governments, all worked to achieve pricereductions.

In May 2000, five pharmaceutical companies offered to negotiate steep cuts in the price of AIDSdrugs for regions severely affected by the AIDS epidemic. Dr. Rolf Krebs, vice chairman ofBoehringer Ingelheim recognised that this was '' the first time that both the public and privatesector are joining forces to implement a major change in the care of HIV/AIDS in the developingworld.'' Although significant price reductions were achieved, the drugs remained prohibitively

expensive for many poor countries. Dr. Peter Piot, the executive director of UNAIDS, called thenegotiations ''a promising step in a long-term process'', whilst Mdecins Sans Frontires calledthe negotiations ''a victory, but a small one, much like an elephant giving birth to a mouse''13.

Around the same time, the Clinton administration issued an executive order which promised thatthe US government would not interfere with African countries that violate American patent lawto obtain cheaper AIDS drugs.
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South African AIDS activists

In 2001 Bill Clinton - following the end of his second term as US president - confirmed hiscommitment to HIV/AIDS drug provision when he established the William J. ClintonFoundation, containing an HIV/AIDS programme. Using the former Presidents contacts and

knowledge, the foundation has continually worked to increase access to HIV treatment bynegotiating pricing deals with drug manufacturers and working to improve health care services indeveloping countries14. Mdecins Sans Frontires does similar advocacy work and runs a majorCampaign for Access to Essential Medicines15.

Another significant event in drug price reduction also came in 2001 following an attempt bythirty-nine major pharmaceutical companies to prosecutethe South African governmentforpassing a law that allowed easy production and importation of generics. Big Pharma waseventually forced to back down and drop the case following a tremendous outcry from theinternational community including the South African government, the European Parliament and300,000 people from over 130 countries who signed a petition against the action. One of the

pharmaceutical companies involved in the case, GlaxoSmithKline, even granted permission(called a voluntary licence) to major South African generics producer Aspen, to share the rightsto their drugs AZT, 3TC and the combination Combivir without charge 16. This was a significantcase as it brought access to medicines for poor countries into the public consciousness.

More recently, in 2006, UNITAID - an international drug purchase facility - was established toensure a stable source of funding for drugs to fight HIV/AIDS, malaria and tuberculosis.UNITAID has partnered with the Clinton Foundation since 2006, negotiating withmanufacturers, including generic producers, to continually lower the price of AIDS drugs andsupply them in over 70 developing countries. They state that they have managed to reduce theprice of leading child HIV treatment regimens by 64 percent and the price of leading adult

regimens by 43 percent in lower-income countries. In 2009, they announced they had reducedthe price of a convenient once-daily pill (combining generic drugs tenofovir, lamivudine andefavirenz) by 30 percent compared to the price they had negotiated in 2008.17 In partnership withdrug manufacturers Pfizer and Mylan, they also brought the price of a second-line therapyregimen to below $500 dollars for the first time. The combination of three pills, available from2010, need to be taken once-daily, and includes an innovative heat resistant pill. It is estimatedthis therapy will result in savings of $400m over five years.18 Through their work, UNITAID andthe Clinton Foundation have encouraged more suppliers to enter into the paediatric and second-line therapy markets which have not been seen by manufacturers as lucrative markets due toconstraints on patent, lower demand, and more complex production techniques.19

Negotiations with Big Pharma have led to a system of tiered pricing. Tiered pricing means thatthe price at which the big pharmaceutical companies sell their drugs is calculated using formulasbased on average income per head, leading to lower prices in poor countries20.

"Preferential pricing is the only way how we can meet both conflicting needs in the

fight against AIDS. We can refinance our high research and development costs for

innovative, new treatments by the established price system in industrialised

countries and can offer affordable medicines to patients in poor countries who
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otherwise cannot afford antiretroviral medication"Alessandro Banchi, chairman of

Boehringer21

Although this system is beneficial to the large pharmaceutical companies, there are concerns thatthe system is overcomplicated and overdependent on the goodwill of Big Pharma.

Sometimes, a country will simply override patent applications by drug manufacturers. In 2009,India rejected patent applications on two antiretroviral drugs, tenofovir and darunavir. Agenerically-produced version of the former drug could cost over five times less than a brandedversion.22The ruling also allows other countries that have rejected patents on these drugs toimport generic versions from India. A representative from Medecins Sans Frontieres said:

This is a really important day for HIV patients in developing countries. The rejection

of the patents on tenofovir opens up the market for new generic competitors to

drive down the price of this key HIV/AIDS drug.23

Another initiative to achieve optimal pricing is The Global Price Reporting Mechanism (GPRM).Launched by the AIDS Medicines and Diagnostics Service (AMDS) in April 2005, themechanism provides information on transaction prices and quantities of antiretroviral drugs inlow and middle income countries.24 This web-based database assists countries in selecting themost affordable drug and supplier. Formed from the information of numerous organisations theGPRM allows a national and international market price comparison. Improving the accesscountries have to market information widens their options whilst placing more pressure onpharmaceutical companies to reduce their pricing.

A study of this database monitored ARV transactions in over 100 countries between 2002 and2008.25 The review indicated significant differences in the prices paid for ARVs and a clear

decrease in the price of ARVs over this time period, particularly in generic ARVs. This fall isbelieved to be associated with, among other reasons, producers of branded ARVs continuing towaiver patents and lower their prices for low income countries as well as ongoing policyformation to address market imperfections.26 However, vast differences in price still exist andpressure to lower the prices of some drugs, notablyprotease inhibitors (PI), is still needed -particularly as the demand for second-line therapy increases.

AIDS, TRIPS and second-line therapy
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Demonstrators protesting

GlaxoSmithKline's policies regarding generic AIDS drugs in Africa

Since 2005, developing countries that are members of the WTO (such as India, Thailand andBrazil) have been required by TRIPS to issue patents. Obliging developing countries to complywith patent legislation has complicated the provision of HIV treatment. This is because although

patents have expired on a number of first-line AIDS drugs (making them available cheaply fromgeneric makers), patents still exist on most new and second-line medicines.

This is problematic as modern antiretroviral drugs are generally less toxic, easier to take andmore effective at fighting HIV. They are often needed when a patient has to change theirantiretroviral regime due to toxicity or resistance. Drugs used to combat resistance are calledsecond-line drugs. They are very important to HIV treatment programmes as 10-15% of peopletaking antiretrovirals will develop resistance to the combination of drugs that they are takingwithin 4-5 years27.

TRIPS has stifled the generic competition that drove the price of first generation antiretrovirals

down, causing huge disparities in the price of first- and second-line ARVs. In 2009 the mediancost of the most commonly used second-line regime was US$853 in low-income countries,US$1378 in lower-middle-income countries, and $US3638 in upper-middle-income countries.28

The vastly more expensive second-line drugs mean that, despite very few people taking them,they still account for a large proportion of the overall drug expenditure. InBrazil, for example,the Ministry of Health currently spends 80% of its budget on imported patented drugs, eventhough they represent only a small proportion of drugs used29.

The consequence of TRIPS is that the new, better drugs are only available in countries that havethe capacity to cover the high cost. Poor countries are forced to wait until their patent expires orthe proprietary prices are forced down. The access gap between people in wealthy and

developing countries has angered many, who feel that TRIPS further exacerbates difficulties insupplying antiretroviral drugs to poor countries and puts the profit margins of Big Pharma beforepublic health. It is felt that if the capacity to provide generic effective, yet cheap anti-AIDStreatment to the developing world exists, then it is immoral not to allow the production of drugsthat will save millions of lives.

"We're starting from zero again by the time generic competition kicks in for the newer drugs,millions of people will have died unnecessarily.
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MSF campaign for access to essential medicines30

In light of these concerns, the WTO proposed two means by which generic versions of drugsunder patents may be produced.

The first is called voluntary licensing. A government, an individual, or an organisation canrequest a voluntary license from a patent holder (usually a large pharmaceutical company) toallow generic drugs to be supplied during a public health emergency, either through imports orby local production. A number of voluntary licenses have been granted to date including alicence granted by Merck for South African generic producer Aspen Pharmacare to produceefavirenz31. The drawback of voluntary licenses is that they depend on the goodwill of the patentholder, and can be lengthy to negotiate.

The second option, compulsory licensing, is discussed below.

Compulsory licensing

Legally a country can get around TRIPS patent enforcement by issuing a compulsory licence. Acompulsory licence is a government licence that enables someone other than the patent holder tocopy patented products and processes without fear of prosecution. Governments can issue themif a patent owner abuses their rights by, for example, failing to offer their product on the market,or offering it at a price that is too high for potential buyers to afford. Normally, to copy drugs forthis reason, the generic company has to negotiate with the original manufacturer to agreeroyalties (money paid to the patent holder to make up for the loss of profit exclusivity).However, following the 2001 Doha agreement a country can issue a compulsory licence for adrug that treats a disease causing a severe health emergency in that country without royaltiesbeing paid.

Although in theory compulsory licensing offers a legal solution to patent protection forHIV/AIDS treatment, in practice it is difficult to exploit for the following reasons:

Generic manufacturers are limited to producing only the quantitiespredefined in each compulsory licence. This curbs the large-scale productionthat is required to deliver drugs cheaply.

Certain large pharmaceutical companies have demonstrated that countriesthat issue compulsory licences may face repercussions (see below).

It was ruled that licences should be granted predominantly to supply thedomestic market, making it difficult for poor countries lacking technologicalcapabilities to access generic drugs manufactured abroad.

This final point was a particular point of contention for those concerned with providing ARVs tothe developing world as it was felt that this effectively penalised the worlds poorest countriesthat were already struggling to roll out HIV treatment.

The World Trade Organization (WTO) therefore issued the so-called paragraph 6 waiver whichallows members who are unable to produce pharmaceuticals at home and are suffering a serious
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health crisis to import generics from other nations under compulsory licences (providingexported drugs are not part of a commercial or industrial policy of the exporting country)32.

Despite endorsement by the WTO, because of its complicated nature, compulsory licensing hasbeen used very little by low- and middle-income countries. In fact, to date Thailand is the only

country to have issued a compulsory licence for an antiretroviral drug and provides an excellentexample of why other countries have been reluctant to follow suit.

Thailand has issued a number of compulsory licences for antiretroviral drugs including Merck &Co.s Sustiva (efavirenz) in 2006 and Abbotts Kaletra (a combination of lopinavir &ritonavir) in 2007.3334 Abbott which is the tenth largest pharmaceutical company in the world -was angered that Thailand had ignor[ed] the patent system and retaliated by announcing that itwould not be applying for licences to sell seven of its newest products in Thailand (one of whichwas a new once-a-day heat resistant form of Kaletra which would have been extremely usefulin the hot Thai climate)35. Thailand has since been repeatedly placed on a US TradeRepresentative 'priority watch list' of countries seen to be committing intellectual property

piracy.

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Although this has been detrimental for Thailand, it has helped to reduce the price ofKaletra by half in many developing countries.38In August 2010, the Thai government extendedcompulsory licensing for Efavirenz and Kaletra until their patents expire (January 2012 forEfavirenz and December 2016 for Kaletra).39

Brazil issued a compulsory license to produce a lower-cost, generic version of Merck'santiretroviral Efavirenz in 2007. Recognising the repercussions that Brazil may face, PresidentLuiz Inacio Lula da Silva said:

Between our trade and our health, we have chosen to look after our health."40

Despite the WTO permitting production of certain ARVs under some conditions, there remainother barriers to their manufacture and distribution. In February 2009 a shipment of second-linegeneric ARV drugs was confiscated by Dutch customs authorities. The 49kg of abacavir sulfatetablets produced by an Indian company, Aurobindo, were bound for a treatment programme inNigeria. The tablets were later released but the seizure highlighted tensions between theEuropean Unions rules on intellectual property rights and World Trade Organization rulesconcerning the production of generic medicines.41

The way forward

For the moment, most people that need antiretrovirals in the developing world have a non drug

resistant form of the virus, and can therefore take first-line therapy. However, as treatmentbecomes more widespread, people stay on treatment for longer and resistance increases, the highprice of second-line drugs is going to become a major issue. Addressing this issue will becomeincreasingly important to ensure the most cost-effective use of available resources and thesustainability of treatment programmes.

Some countries, such as Thailand, Brazil and India have found innovative ways of securingcheaper second-line drugs. But the problem is that these options are limited to countries with
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political clout and financial stability and autonomy. As is all too often the case, it is the poorestcountries already struggling to manage their HIV epidemics that are the least likely to benefitfrom the current system.

This video shows the problems that are preventing people from getting the HIV drugs they

need.

Some have suggested that the only way forward is to abolish the TRIPS system for medicinesaltogether, and replace it with an alternative form of remuneration and reward for innovativeresearch and development. However as this is unlikely, an alternative solution needs to be found.

One initiative created by UNITAID in 2009 is the patent pool".42 The objective of the pool is tohold licences on various patented medicines, which generic companies can then produce at alower cost for poor countries43. Although the creation of a patent pool for HIV/AIDS drugs is atan early stage, there is hope that it will make the production of generic versions of antiretroviralseasier to negotiate and therefore faster and more efficient. The first patent holder to license an

ARV drug to the patent pool is the National Institutes of Health for the drug darunavir.

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However, if the patent pool is to have a real impact it will rely on the voluntary participation oflarger pharmaceutical companies, many of whom may see no benefit in cooperating with it.

Prices of ARVs have been driven down substantially over the years, allowing millions of peopleto live with the virus. However, greater effort, cooperation and innovation is needed to achieveuniversal access to affordable life saving treatment.

Is there a vaccine?

September 2004

No, there is currently no effective vaccine to prevent HIV infection.

Vaccines are used to prevent many different infections in people. Vaccines work by causing a

person's immune system (the body's defense against infections and cancer) to recognize and react to

specific germs. If a person is exposed to one of those germs later, the vaccine may protect them from

getting infected.

Although there are vaccines that prevent other diseases caused by viruses (including hepatitis B,

yellow fever, and even chicken pox), there is no effective vaccine for HIV. Most experts think that a

vaccine is the best long-term hope for controlling HIV around the world. Researchers are working to

develop vaccines for HIV, and several are being tested. It is a difficult process, however, and no one

is sure how long it may take to find an effective vaccine.

While there are medicines that can improve the health of people with HIV, there is no cure for HIV.
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Because there is no vaccine and no cure, it is important that those people who are not infected with

HIV stay uninfected and those living with HIV/AIDS stay healthy.

Discovery May Pave Way to AIDS Vaccine

HIV-Neutralizing Antibodies in Humans Could Play a Key Role in Development of Vaccine

By Daniel J. DeNoon

WebMD Health News

Reviewed by Louise Chang, MD

July 9, 2010 -- National Institutes of Health (NIH) scientists now have "proof" that the search for an AIDS

vaccine can succeed.

In the bloodof an HIV infected person, the researchers discovered two powerful antibodies that neutralize

91% of HIV strains.

"The discoveries we have made may overcome the limitations that have long stymied antibody-based HIV

vaccine design," Peter D. Kwong, PhD, chief of structural biology at the NIH Vaccine Research Center,

says in a news release.

The finding has implications far beyond HIV and AIDS. The new techniques used to find the anti-HIV

antibodies can be used to spur research into vaccines against other diseases that have long stymied

researchers.

It's major news that humans are capable of making antibodies that neutralize the AIDS virus. But finding

antibodies -- even such powerful antibodies as these -- is not the same as finding a vaccine capable of

eliciting the antibodies. It will be years, at least, before the discovery leads to a vaccine that can be tested

in people.

Even so, the discovery of the antibodies was a major scientific feat. The researchers, led by Kwong,

Vaccine Research Center Director Gary J. Nabel, MD, PhD, and Vaccine Research Center Deputy

Director John R. Mascola, MD, used newly developed molecular techniques to build "resurfaced" protein

probes to trap the antibodies.

It seems surprising that a person with HIV infection can carry powerful anti-HIV antibodies and not be

cured. But other recent studies suggest that as many as one in four people with HIV infection may carry

such antibodies.

The problem is that the antibodies appear naturally only long after HIV has established a death grip on

the body. Because the virus replicates often and mutates quickly, people don't just carry a single strain of

HIV -- their blood swarms with a vast number of HIV "quasi-species." By the time a person develops

neutralizing antibodies, the virus has had time to evolve escape variants.

But if a vaccine were able to elicit neutralizing antibodies before a person was exposed to HIV, it's very

likely the antibodies would keep the virus from taking root.
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Physicians offering their patients ARV therapy face an important ethical question: Would it be proper tooffer and initiate a first-line regime when they believe the patients may not be able to afford the laterregimes? This is the same ethical dilemma that they faced a few years ago regarding dual versus tripletherapy.

Another important factor in ensuring the rational use of drugs is the availability of standard guidelines for

their use. Internationally, three organisations, the Health and Human Services (HHS) USA, InternationalAIDS Society (IAS) and British HIV Association (BHIVA) issue guidelines for HIV treatment on a regularbasis. However, most of these guidelines have been developed from research carried out in the West.Some African countries and Brazil have developed their own guidelines to ensure uniformity in use. InIndia, uniform guidelines relevant to our population are not available. Though international guidelines areused, the limitations of applying them to the Indian population need to be acknowledged and addressed.

Training physicians in the prescription of antiretroviral therapy is extremely crucial to ensure the rationaluse of these drugs. Since information about HIV treatment is constantly evolving, frequent updating isnecessary. Only a few, sporadic efforts have been made in this direction. Companies need to do more tocorrectly educate physicians about antiretroviral use. This would involve imparting technical knowledgeand also discussing attitudinal and communication issues, particularly the importance of developing agood rapport with the patient. Additionally, a system of continuing medical education credits needs to be

established.

Rifampicin used for treatment of tuberculosis, the commonest opportunistic infection for AIDS patients,interacts with protease and non-nucleoside reverse transcriptase inhibitors. It reduces the plasma levelsof these antiretroviral drugs leading to development of resistance. Physicians need to be aware of thisinteraction when they plan to offer antiretroviral therapy for HIV-infected patients with tuberculosis.

The saddest part about antiretroviral therapy in India is the unavailability of paediatric formulation of thesedrugs. Neither protease inhibitor nor non-nucleoside reverse transcriptase inhibitor formulations areavailable. This essentially means that children cannot be given a three-drug regime. Neither cannevirapine be given to a neonate born to an HIV-positive mother to reduce the chances of acquiring HIVinfection. Pharmaceutical companies have probably neglected this need because the market forpaediatric formulations is still very small.

Two important surrogate markers, the plasma viral load and the CD4 counts, are used for initiating andmonitoring response to therapy. These tests have to be carried out at frequent intervals and are costly.This cost has to be added to the cost of therapy, but nobody talks about this during drug promotions.Additionally, facilities for performing these tests are available only at a few centres. Often drug therapy isinitiated without doing any of these tests, which is hazardous. It is like managing diabetes withoutmonitoring blood sugar levels. There is also a lot of variability in the test reports from various centres.Uniform quality assurance programmes need to be established and laboratories need to be accredited.

Adherence is critical for the long-term success of antiretroviral therapy. Patients need a lot ofencouragement and support to achieve more than 90 per cent adherence to their regimes. Mechanismsto ensure it need to be built up both by companies and treating physicians. It would be useful tomanufacture a fixed dose combination of these drugs (such as three drugs in a single tablet), to make life

easier for the patient. Another strategy would be to dispense drugs in monthly packs and not sell them inloose strips. Education and support by physicians, coupled with a commitment by patients to continuedespite side effects and inconvenience, has become a critical component of successful treatment.

Hence, there many factors in addition to drug availability which determine the success of antiretroviraltherapy. In the absence of addressing these background factors, reducing the prices and improvingaccess will only contribute to more abuse than rational use. Irrational use may lead to the emergence of amulti-drug resistant HIV epidemic in the future. Moreover, these drugs will be rendered ineffective whenused in pregnant women with the resistant virus to prevent their babies from getting infected.


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What is HIV antiretroviral drug treatment

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